We previously generated DT40 cells in which both alleles of the SIRT6 gene were inactivated by gene targeting, and tested the sensitivity of these cell lines towards DNA damaging agents. In contrast to earlier reports of studies using SIRT6-deficient murine embryonic stem cells, no defects in DNA repair could be identified in this B cell line. Gene expression microarray data indicated, however, that SIRT6 is important for the control of global gene expression. Hundreds of genes were misregulated, and chromatin immunoprecipitation (ChIP) experiments link this observation to changes in histone acetylation patterns. The identification of primary targets of SIRT6 by ChIP-Sequencing suggested that a broad range of genes is regulated by SIRT6. We are now in the process of dissecting the genetic pathways that are controlled by SIRT6 and deciphering how this contributes to controlling cellular responses to stimuli (including stress) and ultimately regulating organismal lifespan. In addition, we continued a collaboration to identify small molecule compounds that can regulate SIRT6 enzyme activity in vitro and in vivo. In this context, we identified fenugrek extract as a potent inhibitor of SIRT6 activity, and the identification of individual compounds that mediate this activity is ongoing.